chr10-43113654-T-C

Variant names:

• chr10-43113654-T-C
• rs77316810
• NM_020975.6:c.1858T>C
• RET p.Cys620Arg

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_ModeratePP5_Strong

The NM_020975.6(RET):c.1858T>C (p.Cys620Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,120 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005404972: Functional studies indicate this variant impacts protein function [PMID:9230192, 17102091]." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C620Y: Pathogenic (ClinVar VariationId 13916, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.C620= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 549782) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 6.52
• Publications: 9 publications found

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

RET Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV005404972: Functional studies indicate this variant impacts protein function [PMID: 9230192, 17102091].; SCV000234932: Published functional studies demonstrate a damaging effect: auto-kinase and phoshorylation activities, increased proliferation activity, impaired protein maturation, decreased cell surface expression, mouse model demonstrating tumorigenesis and intestinal hypoganglionosis (Ito 1997, Chappuis-Flament 1998, Arighi 2004, Carniti 2006, Yin 2007); PMID: 9384613, 9067749, 9230192, 7835899, 18209889, 19853744, 17514199, 17623957, 21986619, 23744765, 30763276, 16158949, 20979234, 29020875, 12711285, 33340421, 7633441, 16565500, 19336503, 18206480, 15355438, 21765987, 18062802, 20152359, 7881414, 22584707, 20516206, 9681852, 7874109, 25694125, 9090527, 9824583, 17021738, 22584721, 25810047, 7915165, 17372903, 18063059, 8909322, 17316110, 14715928, 9879991, 22897442, 31510104, 31447099, 32179705, 33178136, 30787465, 34987852, 17188172, 11955539, 30349395, 27207748, 11564857, 27847096, 19469690, 8918855, 33754314, 17102091, 15744028, 10790203, 14633923; SCV000290535: Experimental studies have shown that this missense change affects RET function (PMID: 9230192, 9879991, 14715928).; SCV002050817: Experimental evidence evaluating an impact on protein function demonstrated that C620R-expressing cells are unable to migrate, differentiate, and be protected from apoptosis in response to GDNF but they possess ligand-independent rapid proliferation activity, providing an explanation for the ability of the variant to lead to both gain- and loss-of-function RET-associated diseases (Mograbi_2001, Arighi_2004).; SCV000967762: "In vitro functional studies provide some evidence that the p.Cys620Arg variant may impact protein function (Arighi 2004, Chappuis-Flament 1998, Ito 1997)."
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 6 pathogenic, 2 benign (OR vs. background: 13.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000003 — very rare for AD+AR gene (base 0.0001, raised to 0.000122 by highest known P/LP ClinVar AF 0.000122) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.C620Y: Pathogenic (ClinVar VariationId 13916, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.C620= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 549782)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (16/16 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RET NM_020975.6	MANE Select	c.1858T>C p.Cys620Arg	missense	Exon 10 of 20	Prot: NP_066124.1 UniProt:
	RET NM_001406743.1		c.1858T>C p.Cys620Arg	missense	Exon 10 of 21	Prot: NP_001393672.1 UniProt:
	RET NM_001406744.1		c.1858T>C p.Cys620Arg	missense	Exon 10 of 20	Prot: NP_001393673.1

RET NM_020975.6

MANE Select

HGVSc / HGVSpc.1858T>Cp.Cys620Arg

Exon rankExon 10 of 20

missense

Prot: NP_066124.1UniProt: P07949-1

RET NM_001406743.1

HGVSc / HGVSpc.1858T>Cp.Cys620Arg

Exon rankExon 10 of 21

missense

Prot: NP_001393672.1UniProt: P07949-1

RET NM_001406744.1

HGVSc / HGVSpc.1858T>Cp.Cys620Arg

Exon rankExon 10 of 20

missense

Prot: NP_001393673.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RET ENST00000355710.8	TSL:5MANE Select	c.1858T>C p.Cys620Arg	missense	Exon 10 of 20	Prot: ENSP00000347942.3 UniProt:
	RET ENST00000340058.6	TSL:1	c.1858T>C p.Cys620Arg	missense	Exon 10 of 19	Prot: ENSP00000344798.4 UniProt:
	RET ENST00000713926.1		c.1729T>C p.Cys577Arg	missense	Exon 10 of 19	Prot: ENSP00000519223.1 UniProt:

RET ENST00000355710.8

TSL:5MANE Select

HGVSc / HGVSpc.1858T>Cp.Cys620Arg

Exon rankExon 10 of 20

missense

Prot: ENSP00000347942.3UniProt: P07949-1

RET ENST00000340058.6

TSL:1

HGVSc / HGVSpc.1858T>Cp.Cys620Arg

Exon rankExon 10 of 19

missense

Prot: ENSP00000344798.4UniProt: P07949-2

RET ENST00000713926.1

HGVSc / HGVSpc.1729T>Cp.Cys577Arg

Exon rankExon 10 of 19

missense

Prot: ENSP00000519223.1UniProt: A0AAQ5BH28

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461120	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000743	AC:3	Hom:0	AN:40384	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41954	0.0000150	1	66886

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Multiple endocrine neoplasia type 2A (3)
3	-	-	Multiple endocrine neoplasia, type 2 (3)
2	-	-	Hirschsprung disease, susceptibility to, 1 (2)
1	-	-	Aganglionic megacolon (1)
1	-	-	Aganglionic megacolon;C4048306:Multiple endocrine neoplasia, type 2 (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
GPN-Star LLR	N/A	-7.5
GPN-Star score	N/A	7.5
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Uncertain	2.7	M
PhyloP100	Uncertain	6.5
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.037	D
Varity_R	N/A	0.98
VESM-3B	Benign	-12

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs77316810;

hg19: chr10-43609102;

COSMIC: COSV60691231;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar